Antithetic

In antithetical analyses of carbon skeletons the synthon approach described in chapter I is used in the reverse order, e.g. 1,3-difunctional target molecules are "transformed" by imaginary retro-aldol type reactions, cyclohexene derivatives by imaginary relro-Diels-Alder reactions. 

Antithetical connections (the reversal of synthetic cleavages) and rearrangements are indicated by a con or rcarr on the double-lined arrow. Here it is always practical to draw right away the reagents instead of synthons. A plausible reaction mechanism may, of course, always be indicated. 

Antithetical functional group interconversions (FGI), additions (FGA), or removals (FOR) are symbolized by the given abbreviations on the double-lined arrow. 

Both items are repeated until the intermediates are reasonably priced commercial starting materials. The resulting antithetic schemes are then evaluated and the most promising ones can be converted into synthetic plans and be investigated in the laboratory. 

The systematic application of both antithetic steps will now be exemplified with the admittedly trivial synthesis of 3-methylbutanal (isovaleraldehyde). Functional group operations would yield the following alternative target molecules ... 

Since (A) does not contain any other functional group in addition to the formyl group, one may predict that suitable reaction conditions could be found for all conversions into (A). Many other alternative target molecules can, of course, be formulated. The reduction of (H), for example, may require introduction of a protecting group, e.g. acetal formation. The industrial synthesis of (A) is based upon the oxidation of (E) since 3-methylbutanol (isoamyl alcohol) is a cheap distillation product from alcoholic fermentation ( fusel oils ). The second step of our simple antithetic analysis — systematic disconnection — will now be exemplified with all target molecules of the scheme above. For the sake of brevity we shall omit the syn-thons and indicate only the reagents and reaction conditions. 

We close the section on open-chain molecules with an example of a trifunctional target molecule. This does not include any fundamentally new problem. In antithetic analysis one simply chooses an appropriate difunctional starting material, which may be further disconnected into monofunctional starting materials. 

From the above discussion it should be obvious that antithetical analysis of difunctional molecules simply is a reversal of the synthesis scheme already described in chapter 1. 

The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or diastereoselective processes) obviously requires the addition of such units retrosynthetically, as illustrated by the antithetic conversion 34 =i> 35. 

Antithetic conversion of a TGT by molecular rearrangement into a symmetrical precursor with the possibility for disconnection into two identical molecules. This case can be illustrated by the application of the Wittig rearrangement transform which converts 139 to 140 or the pinacol rearrangement transform which changes spiro ketone 141 into diol 142. 

Structural symmetry, either in a target molecule or in a subunit derived from it by antithetic dissection, can usually be exploited to reduce the length or complexity of a synthesis. 

Enantioselective processes involving chiral catalysts or reagents can provide sufficient spatial bias and transition state organization to obviate the need for control by substrate stereochemistry. Since such reactions do not require substrate spatial control, the corresponding transforms are easier to apply antithetically. The stereochemical information in the retron is used to determine which of the enantiomeric catalysts or reagents are appropriate and the transform is finally evaluated for chemical feasibility. Of course, such transforms are powerful because of their predictability and effectiveness in removing stereocenters from a target. 

Antithetic Analysis. (Synonymous with Retrosynthetic Analysis) A problem-solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. 

Sir Bernard Lovell, the founder of Britain s Jodrell Bank Observatory, brings our attention to a present development which, unfortunately, does not favor serendipitous discoveries. What he wrote about astronomy in 1984 is certainly valid for chemistry too I was enthusiastic when. .. computers became a major force in astronomical research. .. But even the greatest blessings tend to be mixed. .. Computers are no exception. .. I fear that literal-minded, narrowly focused computerized research is proving antithetical to the free exercise of that happy faculty known as serendipity. .. . 

Carlsson, M.L. On the role of cortical glutamate in obsessive-compulsive disorder and attention-deficit hyperactivity disorder, two phenomenologically antithetical conditions. Acta Psychiatr. Scand. 102 401, 2000. 

Antithetic sampling, 26 1005 Antithrombin, 4 87 Antithrombin III, 72 147 Antithrombolytic agents, 5 170—175, 171-172t... 

---